Original Article
Association of Serum Leptin Level with Obesity in Children with Acute Lymphoblastic Leukemia Zareifar S MD1,*, Shorafa S MD2, Haghpanah S MD1, Karamizadeh Z MD3, Adelian R MD1 1.Hematology Research Center,Pediatric Hematology/Oncology department, Shiraz University of Medical Sciences, Shiraz, Iran. 2.Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran. 3.Division of Pediatric Endocrinology, department of Pediatrics, Shiraz University of Medical sciences, Shiraz, Iran. Received: 26 January 2015 Accepted:18 April 2015
Abstract Background Obesity is a medical problem in survivors of childhood acute lymphoblastic leukemia. Obesity is associated with many complications, so it is important to investigate the respective etiology. Leptin is a protein synthesized in the fatty tissue and is effective in the control of obesity. Survey of leptin in acute lymphoblastic leukemia (ALL) survivors could be helpful in controlling obesity.
Materials and Methods
patients. At the time of diagnosis, 5.66% were overweight or obese, whereas at the end of treatment, approximately 13 patients (24.53%) were overweight or obese. The median and interquartile range (IQR) for blood leptin level were significantly higher for obese patients than other patients (885, 1120 vs. 246, 494 pg/ml), (P=0.030). The median and IQR were also significantly higher in females than in males (861, 969 vs. 204, 267 pg/ml), (P=0.006).
Conclusion
In this prospective study, 53 pediatric patients diagnosed with ALL between 2006 and 2012 from Southern Iran, were enrolled. We examined body mass index (BMI) status and performed laboratory measuring tests including triglyceride, cholesterol, fasting blood sugar, leptin at diagnosis time and then every 6 months and in the last visit.
Obesity is a complication of ALL treatment. It is associated with elevated blood leptin level. Hypothalamus leptin resistance in obese patients should be considered. In each visit, clinicians should weight and their patient’s BMI take into account.
Results
Acute Lymphoblastic Leukemia, BMI, Leptin, Obesity
Participants consisted of 35 male and 18 female
Keywords
*Corresponding Author Zareifar SMD, Pediatric Hematologist-Oncologist, Hematology Research Center, Shiraz University of Medical Sciences, Nemazee Hospital, Shiraz, Iran . E-mail: [email protected]
Introduction The annual incidence of acute lymphoblastic leukemia (ALL), especially from 1975 to 2006, has increased 0.8% per year (1). Medical late effects of ALL, as the most common childhood cancer associated with cure rate of 80%, are noticeable. One or more adverse events occur in 74.1% of the acute leukemia survivors. Defective physical growth, especially obesity was most commonly reported (2). Obesity is
increasingly prevalent in developed societies with considerable morbidity. This is especially important in children with ALL, in whom the metabolic syndrome may begin during therapy, reaching 40% at the end of treatment (3). In different studies, the prevalence of obesity has been reported to be16 to 57 percent among cured patients with ALL (4). Obesity at diagnosis has been even associated with disease prognosis
Iranian Journal of Pediatric Hematology Oncology 2015, Vol5.No3
116
Zareifar et al (5,6). Several mechanisms intervene in the development of obesity in children with ALL. During treatment, patients usually undergo changes in their lifestyles. The loss of physical activity may be due to many factors, including diminished interest in recreational activity and over-protection of the child by parents or caregivers, changes in lifestyle7, diminished exercise capacity, impaired motor function because of steroid-related myopathy, and vincristine-related neuropathy (1,7). Reduced habitual physical activity and over-feeding due to corticosteroid therapy are commonly considered as the main factors responsible for weight gain. Leptin secretion impairment3, cranial radiotherapy, growth hormone insufficiency (4, 8-10) and pathophysiological changes in the cardiorespiratory system7 might also contribute to reduce physical activity leading to obesity. Adipocyte-derived hormone leptin, known as the prototypical adipokine, is the product of the ob gene. It is produced primarily in the adipose tissue but is expressed in a variety of tissues including the placenta, ovaries, mammary epithelium, bone marrow, and lymphoid tissues (11). Leptin reduces the appetite naturally and increases the food intake and energy expenditure. In addition to regulating the body weight, leptin also has been shown to play a regulatory role for stimulation and differentiation within the myeloid, erythroid; and monocyte cell lineages; whereas; the results of its regulatory effects on lymphocytes and related tumor cells have been contradictory (11). In this study, we assessed the leptin level in children with ALL who developed obesity and overweight compared to patients with normal ranged BMI.
Materials and Methods
familial hyperlipidemia, and ALL relapse were excluded. Finally 53 patients completed the study period. Ethics committee approval was obtained by the Research Advisory Council (RAC) at Shiraz University of Medical Sciences. Informed written consents were obtained from the participants. All patients received prednisone, vincristine,and L-asparaginase as induction chemotherapy. In high risk patients, doxorubicine was also added. Most patients received dexamethasone, daunorubicin, doxorubicin, cyclophosphamide, cytarabine, thioguanine methotrexate, and mercaptopurine as consolidation and maintenance therapy. Drugs were dosed by body-surface area. All patients received CNS chemo-prophylaxis with age-adjusted dose of intra-thecal methotrexate. Cranial radiation was administered to most high-risk patients. There were no protocol-required treatment modifications for obesity. Individual reports from the obese patients in the study cohort have been reviewed to assess for off- protocol dose modifications as the result of obesity. BMI percentile chart was calculated from the book 2000 CDC Growth Charts for the United States: Methods and Development. Those with a BMI below the 5th percentile of the normal population were considered low weight and BMI between the 5th to less than 85th percentile, as normal BMI. BMI between 85 to less than 95% was considered as overweight and those equal to or above the 95th percentile were classified as obese. Ten ml fasting blood was collected; the sera were separated and stored at- 20 centigrade to check leptin, insulin, fasting blood sugar (FBS), and total cholesterol, low density lipoprotein (LDL)and high density lipoprotein (HDL) levels. Leptin level (Pg/ml) was measured using enzyme-linked immunosorbent assay (ELISA) method (leptin ELISA kit, Orgenium, Finland) and insulin was also measured by the same method (Monobind, USA).
In this cohort study, 53 pediatric patients with diagnosis of ALL between 2006 and 2012 were enrolled. From a total of 105 ALL pediatric patients referred to the Pediatric Oncology Hospital referral center in Shiraz Southern Iran, 90 patients agreed to take part in this study. The diagnosis of ALL was confirmed with bone Statistical analysis marrow aspiration and biopsy, flowcytometery Data were analyzed by SPSS, v.17. Test of and immunohistochemistry (IHC). Patients normality was performed by Shapiro-Wilk test. younger than 2 years, secondary malignancy, Descriptive data were presented as mean and Down syndrome, hypothyroidism, history of standard deviation in data with normal 117 Iranian Journal of Pediatric Hematology Oncology 2015, Vol5.No3
Association of serum leptin level with obesity in children with acute lymphoblastic leukemia
distribution. In case of non normal distribution, data were summerized as median and interquartile range (IQR). Comparison of qualitative data between two groups was done using Chi-square test. Quantitative data were compared by Student t-test and Mann-Whitney test as appropriate between two groups of patients. Correlation of leptin and insulin levels was assessed by Pearson Correlation test. Comparison of BMI of different occasions with baseline was done by Paired t-test. P value less than 0.05 was considered statistically significant.
Results Thirty five (66%) patients were male and 18 (34%) female. The mean age at diagnosis was 6 ±3.9 years, ranged from 2 to16.4 years and the average duration of the follow-up was 41.6 ± 18.6 months, ranged from 6 to 89 months. The mean age at the last follow-up was 9.45± 4.2 years (range: 2.8-18.8 years). Ten (18.9%) out of 53 ALL treated children received cranial radiotherapy, consisting of 8males and 2 females.The patients’ characteristics are shown in Table I. Obesity and BMI: At the time of diagnosis, 94.34% of the patients were normal or underweight;whereas; 5.7% were overweight or obese. Meanwhile, at the last follow up, these rates reached 75.5% and 24.5%, respectively. The difference was statistically significant (P = 0.04). Compared with BMI at diagnosis, increasing BMI was statistically significant after 6 months of starting treatment (15.5 vs. 17.1) (P< 0.001). (Fig1) In the second 6 months after starting the treatment, BMI decreased slightly (P=0.02), but 2 years after treatment, it significantly increased (P=0.001). During 24 to 36 months after the diagnosis, BMI exhibited a decline that was not statistically significant (P=0.15).The BMI at diagnosis was significantly different from its increment at 6, 12, 18, 24, 30, and 36 months
after treatment (P
Association of Serum Leptin Level with Obesity in Children with Acute Lymphoblastic Leukemia Zareifar S MD1,*, Shorafa S MD2, Haghpanah S MD1, Karamizadeh Z MD3, Adelian R MD1 1.Hematology Research Center,Pediatric Hematology/Oncology department, Shiraz University of Medical Sciences, Shiraz, Iran. 2.Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran. 3.Division of Pediatric Endocrinology, department of Pediatrics, Shiraz University of Medical sciences, Shiraz, Iran. Received: 26 January 2015 Accepted:18 April 2015
Abstract Background Obesity is a medical problem in survivors of childhood acute lymphoblastic leukemia. Obesity is associated with many complications, so it is important to investigate the respective etiology. Leptin is a protein synthesized in the fatty tissue and is effective in the control of obesity. Survey of leptin in acute lymphoblastic leukemia (ALL) survivors could be helpful in controlling obesity.
Materials and Methods
patients. At the time of diagnosis, 5.66% were overweight or obese, whereas at the end of treatment, approximately 13 patients (24.53%) were overweight or obese. The median and interquartile range (IQR) for blood leptin level were significantly higher for obese patients than other patients (885, 1120 vs. 246, 494 pg/ml), (P=0.030). The median and IQR were also significantly higher in females than in males (861, 969 vs. 204, 267 pg/ml), (P=0.006).
Conclusion
In this prospective study, 53 pediatric patients diagnosed with ALL between 2006 and 2012 from Southern Iran, were enrolled. We examined body mass index (BMI) status and performed laboratory measuring tests including triglyceride, cholesterol, fasting blood sugar, leptin at diagnosis time and then every 6 months and in the last visit.
Obesity is a complication of ALL treatment. It is associated with elevated blood leptin level. Hypothalamus leptin resistance in obese patients should be considered. In each visit, clinicians should weight and their patient’s BMI take into account.
Results
Acute Lymphoblastic Leukemia, BMI, Leptin, Obesity
Participants consisted of 35 male and 18 female
Keywords
*Corresponding Author Zareifar SMD, Pediatric Hematologist-Oncologist, Hematology Research Center, Shiraz University of Medical Sciences, Nemazee Hospital, Shiraz, Iran . E-mail: [email protected]
Introduction The annual incidence of acute lymphoblastic leukemia (ALL), especially from 1975 to 2006, has increased 0.8% per year (1). Medical late effects of ALL, as the most common childhood cancer associated with cure rate of 80%, are noticeable. One or more adverse events occur in 74.1% of the acute leukemia survivors. Defective physical growth, especially obesity was most commonly reported (2). Obesity is
increasingly prevalent in developed societies with considerable morbidity. This is especially important in children with ALL, in whom the metabolic syndrome may begin during therapy, reaching 40% at the end of treatment (3). In different studies, the prevalence of obesity has been reported to be16 to 57 percent among cured patients with ALL (4). Obesity at diagnosis has been even associated with disease prognosis
Iranian Journal of Pediatric Hematology Oncology 2015, Vol5.No3
116
Zareifar et al (5,6). Several mechanisms intervene in the development of obesity in children with ALL. During treatment, patients usually undergo changes in their lifestyles. The loss of physical activity may be due to many factors, including diminished interest in recreational activity and over-protection of the child by parents or caregivers, changes in lifestyle7, diminished exercise capacity, impaired motor function because of steroid-related myopathy, and vincristine-related neuropathy (1,7). Reduced habitual physical activity and over-feeding due to corticosteroid therapy are commonly considered as the main factors responsible for weight gain. Leptin secretion impairment3, cranial radiotherapy, growth hormone insufficiency (4, 8-10) and pathophysiological changes in the cardiorespiratory system7 might also contribute to reduce physical activity leading to obesity. Adipocyte-derived hormone leptin, known as the prototypical adipokine, is the product of the ob gene. It is produced primarily in the adipose tissue but is expressed in a variety of tissues including the placenta, ovaries, mammary epithelium, bone marrow, and lymphoid tissues (11). Leptin reduces the appetite naturally and increases the food intake and energy expenditure. In addition to regulating the body weight, leptin also has been shown to play a regulatory role for stimulation and differentiation within the myeloid, erythroid; and monocyte cell lineages; whereas; the results of its regulatory effects on lymphocytes and related tumor cells have been contradictory (11). In this study, we assessed the leptin level in children with ALL who developed obesity and overweight compared to patients with normal ranged BMI.
Materials and Methods
familial hyperlipidemia, and ALL relapse were excluded. Finally 53 patients completed the study period. Ethics committee approval was obtained by the Research Advisory Council (RAC) at Shiraz University of Medical Sciences. Informed written consents were obtained from the participants. All patients received prednisone, vincristine,and L-asparaginase as induction chemotherapy. In high risk patients, doxorubicine was also added. Most patients received dexamethasone, daunorubicin, doxorubicin, cyclophosphamide, cytarabine, thioguanine methotrexate, and mercaptopurine as consolidation and maintenance therapy. Drugs were dosed by body-surface area. All patients received CNS chemo-prophylaxis with age-adjusted dose of intra-thecal methotrexate. Cranial radiation was administered to most high-risk patients. There were no protocol-required treatment modifications for obesity. Individual reports from the obese patients in the study cohort have been reviewed to assess for off- protocol dose modifications as the result of obesity. BMI percentile chart was calculated from the book 2000 CDC Growth Charts for the United States: Methods and Development. Those with a BMI below the 5th percentile of the normal population were considered low weight and BMI between the 5th to less than 85th percentile, as normal BMI. BMI between 85 to less than 95% was considered as overweight and those equal to or above the 95th percentile were classified as obese. Ten ml fasting blood was collected; the sera were separated and stored at- 20 centigrade to check leptin, insulin, fasting blood sugar (FBS), and total cholesterol, low density lipoprotein (LDL)and high density lipoprotein (HDL) levels. Leptin level (Pg/ml) was measured using enzyme-linked immunosorbent assay (ELISA) method (leptin ELISA kit, Orgenium, Finland) and insulin was also measured by the same method (Monobind, USA).
In this cohort study, 53 pediatric patients with diagnosis of ALL between 2006 and 2012 were enrolled. From a total of 105 ALL pediatric patients referred to the Pediatric Oncology Hospital referral center in Shiraz Southern Iran, 90 patients agreed to take part in this study. The diagnosis of ALL was confirmed with bone Statistical analysis marrow aspiration and biopsy, flowcytometery Data were analyzed by SPSS, v.17. Test of and immunohistochemistry (IHC). Patients normality was performed by Shapiro-Wilk test. younger than 2 years, secondary malignancy, Descriptive data were presented as mean and Down syndrome, hypothyroidism, history of standard deviation in data with normal 117 Iranian Journal of Pediatric Hematology Oncology 2015, Vol5.No3
Association of serum leptin level with obesity in children with acute lymphoblastic leukemia
distribution. In case of non normal distribution, data were summerized as median and interquartile range (IQR). Comparison of qualitative data between two groups was done using Chi-square test. Quantitative data were compared by Student t-test and Mann-Whitney test as appropriate between two groups of patients. Correlation of leptin and insulin levels was assessed by Pearson Correlation test. Comparison of BMI of different occasions with baseline was done by Paired t-test. P value less than 0.05 was considered statistically significant.
Results Thirty five (66%) patients were male and 18 (34%) female. The mean age at diagnosis was 6 ±3.9 years, ranged from 2 to16.4 years and the average duration of the follow-up was 41.6 ± 18.6 months, ranged from 6 to 89 months. The mean age at the last follow-up was 9.45± 4.2 years (range: 2.8-18.8 years). Ten (18.9%) out of 53 ALL treated children received cranial radiotherapy, consisting of 8males and 2 females.The patients’ characteristics are shown in Table I. Obesity and BMI: At the time of diagnosis, 94.34% of the patients were normal or underweight;whereas; 5.7% were overweight or obese. Meanwhile, at the last follow up, these rates reached 75.5% and 24.5%, respectively. The difference was statistically significant (P = 0.04). Compared with BMI at diagnosis, increasing BMI was statistically significant after 6 months of starting treatment (15.5 vs. 17.1) (P< 0.001). (Fig1) In the second 6 months after starting the treatment, BMI decreased slightly (P=0.02), but 2 years after treatment, it significantly increased (P=0.001). During 24 to 36 months after the diagnosis, BMI exhibited a decline that was not statistically significant (P=0.15).The BMI at diagnosis was significantly different from its increment at 6, 12, 18, 24, 30, and 36 months
after treatment (P
